MACFARLANE All of my research came from “The Astronaut’s Wife.” It was the same process I used for “Ted”: It was important that this be somebody who was able to bring a sincerity to the character, and the jokes carry themselves if you have that.

This is a period comedy set in the Wild West, and Charlize, you’re a female gunslinger?

THERON She married into that world at a young age and got stuck in a life that really wasn’t her own. Through circumstances, she finds herself outside of that life for a split second and gets to really see the potential of something different and better, and tries to go after that.

And Seth, your character is a coward who needs Charlize’s help?

MACFARLANE That wasn’t much of a stretch for me. I won’t even get on the freeway without my navigator. There was a parallel between my personal experience on the movie, for my virgin effort at being on camera, and the story itself. As we went along, Charlize was the one person I could quietly turn to, and say, “Hey, did that seem good to you, or was it too James Brolin?” I don’t know why I just said that. He’s never done anything to me. Sorry, James Brolin, I think you’re great.

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Clip: ‘A Million Ways...’

A scene from “A Million Ways to Die in the West,” directed by Seth MacFarlane.

By Universal Pictures on Publish Date May 28, 2014.
Photo by Lorey Sebastian/Universal Pictures.
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THERON I’d gone through like a two-year period where I wasn’t really enjoying making movies anymore. And this movie really just shook me and made me realize how much I love it. I owe a lot of that to Seth.

Even after he included you in his opening number at the Oscars?

THERON Don’t talk [trash] about him, O.K.? [laughter] I’ve given you an answer. Take that and don’t talk [trash].

A version of this article appears in print on May 4, 2014, on Page AR30 of the New York edition with the headline: Seth MacFarlane and Charlize Theron. Order Reprints|Today's Paper|Subscribe